The long-term objective of this research is to understand the mechanism of glucocorticoid resistance in tumor cells. In this study, I will seek direct evidence for the involvement of membrane proteins in the generation of the lethal effects of glucocorticoids in normal and neoplastic cells. An important objective of this research will be the examination of the hypothesis that resistance in the P1798 lymphosarcoma line is due, not to a lack of hormone receptors, but rather to a difference in the hardiness of the nuclear, or possibly plasma, membranes. The approach will be to examine total cellular proteins via the two dimensional gel electrophoresis technique (developed by O'Farrell) by which more than 1,000 radiolabelled proteins from lymphoid cells can be separated. I intend to study the involvement of cellular proteins in the generation of the lethal effects of glucocorticoids on normal thymic lymphocytes and P1798 lymphosarcoma cells. Emphasis will be placed upon the relationship between the protein constituents of the cellular membranes and mechanisms for the emergence of resistance to glucocorticoid killing.